HRP960547A2 - Substituted benzodicarboxylic acid diguanidines, process for their preparation, and their use as medicament or diagnostic agent, and medicaments containing them - Google Patents

Description

The invention relates to benzenedicarboxylic acid diguanides of formula I

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in which one of the residues R(1), R(2), R(3) and R(4) represents -CO-N=C(NH2)2;

and from the remaining residues R(1), R(2), R(3) and R(4)

R(1) represents hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, J, -OR(32), -NR(33)R(34) or CF3;

R(32), R(33) and R(34) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

R(2) and R(4) independently represent hydrogen, F, Cl, Br, J, OH, -CN, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 C-atoms or (CH2)m-R(14);

m is 0, 1 or 2

R(14) represents -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy and -NR(15)R( 16);

R(15) and R(16) represent hydrogen or -CH3; or

R(2) and R(4) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C8)-Alkanoyl, (C2-C8)-Alkoxycarbonyl, Formyl, Carboxy, -CF3, Methyl, Methoxy;

R(2) and R(4) independently represent R(22)SO2, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-SO2 ;

R(22) and R(28) independently of each other represent methyl or -CF3;

R(23), R(24), R(29) and R(30) independently represent hydrogen or methyl; or

R(2) and R(4) independently represent -OR(35) or -NR(35)R(36);

R(35) and R(36) independently represent hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; or

R(35) and R(36) together represent 4-7 methylene groups of which one CH2 group can be substituted with oxygen, -S-, -NH-, -NCH3 or -N-benzyl;

R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);

R(25) represents hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms or renyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and diethylamino;

or

R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or unsubstituted by 1-3 substituents selected from the group consisting of F, Cl, Cf3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino;

R(26) and R(21) are independently defined as R(25) or represent hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R(5) represents alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, J, X-(CH2)y-CF3 or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from groups consisting of F and Cl, CF3, methyl, methoxy and -NR(6)R(7);

R(6) and R(7) independently represent -CH3;

X represents a single bond or oxygen;

y is zero, 1 or 2; and their pharmaceutically acceptable salts.

Particular preference is given to compounds of formula I in which one of the residues R(1), R(2), R(3) and R(4) represents -CO-N=C(NH2)2

and from the remaining residues R(1), R(2), R(3) and R(4)

R(1) represents hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, -OR(32), -NR(33)R(34) or CF3;

R(32), R(33) and R(34) independently represent hydrogen or methyl;

R(2) and R(4) independently represent hydrogen, F, Cl, Br, J, OH, CF, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, alkenyl with 2, 3 or 4 carbon atoms or -(CH2)m-R(14);

m is zero, 1 or 2;

R(14) represents -(C3,-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy;

R(2) and R(4) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-Alkanoyl, (C2-C5)-Alkoxycarbonyl, formyl, carboxy, -CF3 and methyl;

or

R(2) and R(4) independently represent R(22)-SO2-, R(26)-CO- or R(29)R(30)N-SO2;

R(22) and R(26) independently represent methyl or CF3;

R(29) and R(30) independently represent hydrogen or methyl;

or

R(2) and R(4) independently represent -OR(35) or -NR(35)R(36);

R(35) and R(36) independently represent hydrogen, methyl or ethyl;

or

R(35) and R(36) together represent 4-5 methylene groups of which one CH2 group can be substituted with oxygen., -S-, -NH-, -NCH3;

R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25) R(26) R(27);

R(25) represents hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or phenyl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;

or

R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with 1-2 substituents

Selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;

R(26) and R(27) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms;

R(5) represents alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, CF3 or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F and Cl, -CF3 , methyl, methoxy and dimethylamino; and their pharmaceutically acceptable salts.

Particular preference is given to compounds of formula I in which one of the residues R(1), R(2), R(3) and R(4) represents -CO-N=C(NH2)2

and from the remaining residues R(1), R(2), R(3) and R(5)

R(1) represents hydrogen, alkyl with 1, 2, 3 or 4 C-atoms,

R(32), R(33) and R(34) independently represent hydrogen or methyl

R(2) and R(4) independently represent hydrogen, F, Cl, OK, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, or pyrrole-1 -yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanolyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF2 and methyl;

or

R(2) and R(4) represent R(22)-SO2-;

R(22) represents methyl or –CF3;

or

R(2) and R(4) independently represent -OR(35) or -NR(35)R(36);

R(35) and R(36) independently represent hydrogen, methyl or ethyl;

R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);

R(25) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or

R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

R(26) and R(27) independently represent hydrogen or methyl;

R(5) represents alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3 or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; and their pharmaceutically acceptable salts.

Compounds of formula I are particularly preferred, in which one of the residues R(1), R(2), R(3) and R(4) represents -CO-N=C(NH2)2;

and from the remaining residues R(1), R(2), R(3) and R(4)

R(1) represents hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, F, Cl, CF3, or methoxy;

R(2) and R(4) independently represent hydrogen, OH, CF2, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, or pyrrole-1-yl, which unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl ;

R(3) represents hydrogen, -OR(25) or -CR(25)R(26)R(27);

R(25) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

or

R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3;

R(26) and R(27) independently represent hydrogen or methyl;

R(5) represents alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3 or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F and Cl, CF3 and methyl; and their pharmaceutically acceptable salts.

The indicated alkyl residues can be straight or branched chain.

By (C1-C9)-heteroaryl are meant residues derived from phenyl or naphthyl, in which one or more CH groups are replaced by N and/or in which at least two adjacent CH groups are replaced by S, NH or O (with formation of a five-membered aromatic ring). Of the others, one or both atoms of the condensation site may also be N-atoms of a bicyclic residue (as in indolizinyl).

Heteroaryls are understood in particular to be furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oscasolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoyl, quinolyl, isoquinol, phthalazinyl, quinoxalinyl, quinoxazolinyl, quinolinyl .

If one of the substituents R(1) to R(5) has one or more centers of asymmetry, they can independently be in the S or R configuration. The compounds may also exist as optical isomers, as diastereomers, as racemates or as mixtures thereof.

The invention further relates to the process for the production of compounds i, which is characterized by the fact that the compound of formula II

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in which R(1) to R(5) have the meanings given above for R(1) to R(5), of which however at least one of the substituents R(1) to R(5) represents the indicated COL group, wherein L represents a nucleophilic leaving group that can be easily substituted, chemically transformed with guanidine.

Activated acid derivatives of the formula II, in which L represents alkoxy, preferably a methoxy group or a phenoxy group, a phenylthio, a methylthio, a 2-pyridylthio group, or a beterocycle with nitrogen, preferably 1-imidazolyl, are primarily obtained in a known manner from basic carboxylic acid chlorides (formula II, L=Cl), which in turn can be produced in a known manner from basic carboxylic acids (formula II, L=OH), for example with thionyl chloride.

In addition to chlorides of carboxylic acids of the formula II (L=Cl), further activated acid derivatives can also be produced directly from the basic derivatives of benzoylcarboxylic acid (formula II, L=OH), such as, for example, the meryl ester of the formula II with L=OCH3 by treatment with gaseous HCl in methanol, imidazole of formula II by treatment with carbonyldiimidazole [L=1-imidazole, Staab, Angew. Chem. Int. Ed. English 1351-367(1962)], mixed anhydrides II with Cl-COOC2H5 or with tosyl chloride in the presence of triethylaramine in an inert solvent, as well as by activating benzenedicarboxylic acid with dicyclohexylcarbodilmide (DCC) or with O-[(cyano(ethoxy -carbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate ("TOTU") [Proceedings of the 21. Europien Peptide Symposium, Peptides 1990, Publishers E. Giralt and D. Ar;drou, Escom, Leiden , 1991]. A number of suitable methods for the production of activated derivatives of carboxylic acids of general formula II are listed in the literature review in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985, p. 350.

The chemical conversion of activated carboxylic acid derivatives of formula I with guanidine takes place in a manner known per se in a protic or aprotic polar but inert organic solvent. At the same time, when converting the methyl ester of benzenedicarboxylic acid (II, L=OMe) with guanidine, methanol, isopropanol or THF at a temperature of 20°C to the boiling point of that solvent proved to be good. In most chemical transformations of compounds II with guanidine, when not in salt form, it is useful to work in inert solvents such as THF, dimethoxyethane, dioxane or isopropanol. Water can also serve as a solvent.

Kdd is L = Cl, it is useful to work with the addition of an acid acceptor, for example, in the form of excess guanidine, for

Binding of hydrohalic acid.

The introduction of compounds substituted in the phenyl part with sulfur, oxygen or nitrogen nucleophiles is carried out by nucleophilic substitution on dialkyl ester derivatives of benzenedicarboxylic acid according to methods known from the literature. In this substitution, halides and trifluoromethanesulfonates proved to be good starting groups on the benzene-dicarboxylic acid derivative. It is preferably carried out in a dipolar aorotic solvent, such as DMF or TMU, at a temperature from 0°C to the boiling point of the solvent, preferably from 80°C to the boiling point of the solvent. An alkaline or alkaline earth salt with an anion of high basicity and slight nucleophilicity, for example k2CO3 or CsCO3, serves as an acid acceptor.

The introduction of alkyl and aryl substituents is done by cross-linking aryl halides with, for example, organic zinc compounds, organic tin compounds, organic boric acid compounds or organoboranes via palladium, according to methods known from the literature.

Diguanides of benzenedicarboxylic acid I are generally weak bases and can bind acids to form salts. Suitable acid addition salts are salts of all pharmacologically tolerable acids, for example halides, especially hydrochlorides, ascorbates, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonatiptoluosulfonates.

In the patent document WO 94/26709, diguanides of benzenedicarboxylic acid are described, among which none of the compounds have the substituents R(5) indicated here, which correspond to the substituent R(3) from that patent document.

Surprisingly, it was found that the introduction of certain substituents R(1) and/or R(5) significantly increases the efficiency of the compounds and thus positively affects their pharmacokinetics.

Due to their pharmacological properties, the compounds are extremely suitable as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of heart attacks and the treatment of heart attacks, and for the treatment of angina pectoris, whereby they also prevent or greatly reduce the pathophysiological processes in the occurrence of ischemic-induced injuries, especially in the occurrence of cardiac arrhythmias induced ischemia. Due to their protective action against pathological hypoxic and ischemic situations, compounds according to the invention of formula I, due to the inhibition of the cellular mechanism of Na+/H+ exchange, can be used as drugs for the treatment of all acute or chronic injuries caused by ischemia or primary or secondary diseases induced thereby. This refers to their use as drugs in surgical procedures, e.g. in organ transplants, whereby the compounds can be used to protect organs in the donor, before and during retrieval, to protect removed organs, e.g. for processing or their disposal in physiological liquid baths , as well as when transferring to the recipient's organism. The compounds are also valuable drugs with a protective effect during angioplasty operations, for example on the heart, as well as on peripheral blood vessels. In accordance with their protective action against ischemia-induced injuries, the compounds are also suitable as drugs for the treatment of the nervous system, especially the central nervous system, where they are suitable, for example, for the treatment of stroke or brain edema. The compounds according to the invention of formula I are also suitable for the treatment of forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

Furthermore, the compounds according to the invention of formula I are characterized by a slight inhibitory effect on cell proliferation, for example the proliferation of fibroblast cells and the proliferation of smooth muscle cells of blood vessels. For this reason, the compounds of the formula come into consideration as valuable therapeutics for diseases in which cell proliferation is the primary or secondary cause, and for this reason they can be used as antiatherosclerotics, agents against diabetic late complications, cancer, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or fibrosis kidney, organ hypertrophy or hyperplasia, especially in prostate hyperplasia or prostate hypertrophy.

The compounds according to the invention are effective inhibitors of cellular sodium-proton antiporters (Na+/H+ exchangers) which are also elevated in such cells in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.), measurements are easily available, for example in erythrocytes, platelets or leukocytes. The compounds according to the invention are therefore suitable as a distinguished and simple scientific tool, for example for use in diagnostics to determine and distinguish between advanced forms of hypertension, but also for atherosclerosis, diabetes, proliferative diseases, etc. Furthermore, the compounds of formula I are suitable for preventive therapy to prevent genesis of high blood pressure, for example essential hypertension.

Compared to most known compounds, the compounds according to the invention have significantly better solubility in water. This is why they are much better for i.v. application.

Compared to known water-soluble compounds, the compounds according to the invention are characterized by excellent bioavailability and pharmacokinetics.

Hereby, drugs containing compound I can be administered orally, parenterally, intravenously, rectally or by inhalation, whereby the preferred application depends on the relevant disease presentation. Here, compounds I can be used alone or together with galenic excipients, both in veterinary medicine and in human medicine.

Excipients suitable for the desired drug formulation are known to the expert based on his professional knowledge. In addition to solvents, agents for forming gels, bases for suppositories, excipients for tablets and other active substance carriers, antioxidants, dispersants, emulsifiers, anti-foaming agents, taste-correcting agents, preservatives, and dissolution-accelerating agents can be used, for example. or dyes.

For oral application, the active compounds are mixed with suitable additional substances, such as carrier substances, stabilizers or inert diluting agents, and are translated by usual methods into forms suitable for administration, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions. Gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used as inert carriers. At the same time, the preparation can be dry or also a wet granulate. Vegetable or animal oils, such as sunflower oil or fish liver oil, can be used as oil carriers or solvents.

For subcutaneous or intravenous administration, the active compounds are if desired, with the usual substances, such as agents for promoting dissolution, emulsifiers or other auxiliary substances, they are translated into solutions, suspensions or emulsions. Suitable solvents include, for example, water, physiological saline solution or alcohols, for example ethanol, propanol, glycerin, and also sugar solutions, such as glucose or mannitol solutions, or also a mixture of different mentioned solvents.

As pharmaceutical formulations for administration in the form of an aerosol or spray, solutions, suspensions or emulsions of the active substance of formula I in a pharmaceutically acceptable solvent, especially ethanol or water, or a mixture of such solvents are suitable. If necessary, the formulation can also contain other pharmaceutical auxiliary substances such as surfactants, emulsifiers and stabilizers, and propellant gas. Such a preparation contains the active substance usually in a concentration of about 0.1 to 10, especially from about 0.3 to 3 wt. %.

The dosages of the active substance of formula I when administered and the frequency of administration depend on the strength of action and duration of action of the compound used, and in addition also on the type and severity of the treated disease, and on the type, age, weight and individual irritability of the treated mammal.

On average, the daily dose of the compound of formula I in a patient weighing approximately 75 kg is at least 0.001 mg/kg body weight, preferably at least 0.01 mg/kg body weight, up to 10 mg/kg body weight, preferably up to 1 mg/kg body weight weight. In acute disease outbreaks, approximately immediately after suffering a heart attack, higher and above all more frequent dosages may be required, for example up to 4 individual doses per day. Especially with i.v. application, possibly in a patient with a heart attack in the intensive care unit, up to 100 mg per day may be necessary.

List of abbreviations:

AIBN α,α-azo-bis-isobutyronitrile

Bn benzyl

A saturated aqueous solution of NaCl is concerned

CH2Cl2 dichloromethane

DCT desorption chemical ionization

DTP diisopropyl ether

DMA dimethylacetamide

DME dimethoxyethane

DMF N,N-dimethylformamide

EE ethyl acetate (EtOAc)

EI electron impact

Eq. equivalent

ES ionization by electrospray

Et ethyl

FAB bombing with fast atoms

HEP n-heptane

HOAc acetic acid

Me methyl

MeOH methanol

mp melting point

MTB methyl tert.butyl ether

NBS N-bromosuccinimide

NMP N-methylpyrrolidone

RT room temperature

THF tetrahydrofuran

TMU N,N,N',N'-tetramethylurea

Tol toluene

CNS central nervous system

Experimental part

General regulation for the production of diguanide of benzenedicarboxylic acid (I) from dialkylester of benzenedicarboxylic acid (II, L=O-alkyl)

5 mmol of dialkyl ester of benzoic acid formula II and 50 mmol of guanidine (free base) are dissolved in 5 ml of isopropanol and boiled under reflux until complete chemical conversion (thin-layer control) (typical reaction time is from 5 minutes to 5 hours). At the end, it is diluted with 150 ml of water and the product is sucked off. If necessary, chromatograph on silica gel with a suitable eluent, eg EE/MeOH 5:1.

Example 1

Diguanidide of 4-chloro-5-phenyl-isophthalic acid

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3-bromo-2-chloro-5-methyl-benzoic acid

25 g of 2-amino-3-bromo-5-methyl-benzoic acid in 500 ral of 6 N aqueous HCl solution is diazotized at 0°C with 8.3 g of NaNO2, then mixed for 30 minutes at room temperature and poured into the solution in portions , heated to 40°C, of 22 g of CuCl in 200 ml of a saturated aqueous solution of HCl. It is stirred for another 20 minutes at 40-50°C, the precipitate is suctioned off, washed with water until neutral and dried at 40°C under reduced pressure. 23.3 g of pale yellow crystals are obtained, melting point 170-172°C

Rf(EE/MeOH 5:1)=0.51

MS(DCI): 249(M+H)+

b) 5-bromo-4-chloro-isophthalic acid

Dissolve 99 g of MaSO4·7H2O in 600 ml of water, then add 20 g of 3-bromo-2-chloro-5-methyl-benzoic acid, heat to 90°C, then add in portions at 90-100°C 63 g of KMnO4 and stirred for 2 hours under reflux. Finally, it is allowed to cool to room temperature, a saturated aqueous solution of Na2SO3 is added drop by drop until the purple color disappears, with a saturated aqueous solution of Na2O3 it is adjusted to pH=12 and the MnO2 is sucked off. It is washed with a saturated aqueous Na2CO3 solution and with hot water, the filtrate is adjusted to pH=1 with an aqueous HCl solution and the precipitate is suctioned off. 13.5 g of colorless crystals are obtained, melting point >275°C.

Rf(DlP/2% HOAc)=0.16

MS(DS): 279(M+H)+

c) Dimethyl ester of 5-bromo-4-chloro-isophthalic acid

Dissolve 13.3 g of 5-bromo-4-chloro-isophthalic acid in 200 ml of MeOH, add 20 ml of SOCl2 dropwise and stir for 5 hours under reflux. Finally, the volatile ingredients are removed in a vacuum and the residue is dried in a fine vacuum. 14 g of colorless crystals are obtained, melting point 99°C.

MS(DCI): 307(M+H)+

d) Dimethyl ester of 4-chloro-5-phenyl-isophthalic acid

Mix 3.1 g of dimethyl ester of 5-bromo-4-chloro-isophthalic acid, 1.2 g of benzeneboric acid, 2.1 g of Na2CO3, 230 mg of Pd(OAc)2 and 500 mg of triphenylphosphine in 50 ml of toluene and 10 ml of water. for 6 hours under reflux. Allow to cool to room temperature, dilute with 300 ml of toluene and wash 3 times with 100 ml of saturated aqueous Na2CO3 solution each. It is dried over Na2SO4, the solvent is removed in vacuo and then chromatographed on silica gel with EE/HEP 1:4. 1.5 g of colorless oil is obtained.

Rf EE/HEP 1:4)=0.22

MS(DCI): 305(M+H)+

e) Diguanidide of 4-chloro-5-phenyl-isophthalic acid

2.6 g of potassium tert.butylate are dissolved in 50 ml of anhydrous DMF and mixed with 2.6 g of guanidine hydrochloride. It is stirred for 1.5 hours at room temperature, 700 mg of 4-chloro-5-phenyl-isophthalic acid is added and stirred for 2 hours at 100°C. The mixture is poured over 1 liter of water, adjusted to pH=8 with aqueous NaHCO3 solution and aqueous HCl solution and then extracted three times with 200 ml EE each. It was dried over Na2SO4 and the solvent was removed in vacuo. The residue is suspended in 100 ml of water and suction, finally the precipitate is suspended again in 50 ml of EE and suction. The product is dried in a vacuum and 350 mg of colorless crystals are obtained, melting point 235°C (decomposition).

Rf(acetone/water 10:1)=0.063

MS(ES): 359(M+H)+

Pharmacological data

Inhibition of Na+/H+-exchanger in rabbit erythrocytes

White New Zealand rabbits (Ivanovas) were fed a standard diet with 2% cholesterol. during six weeks in order to activate the Na+/H+-exchange and thus be able to determine the entry of Na+ into erythrocytes by means of flame photometry. Blood was taken from the ear arteries and clotting was prevented with 25 IU of cealium-heparin. One portion of each sample was used for double hemacrodite determination by centrifugation. Aliquots of 100 µl were used to measure the initial content of Na+ in erythrocytes.

To determine amiloride-sensitive sodium entry, 100 µl of each blood sample was incubated in 5 ml of hyperosmotic salt-sucrose solution (mmol/1:140 NaCl, 3 KCl, 150 sucrose, 0.1 oubain, 20 tris-hydroxymethyl-aminomethane) at pH 7.4 and 37°C. After that, the erythrocytes were washed three times with ice-cold MgCl2-oubain solution (mmol/1: 112 MgCl2 0.1 oubain) and hemolyzed in 2.0 ml of distilled water. Intracellular sodium content was determined by flame photonometry.

Na+ entry was calculated as the difference between the initial value of sodium content and the sodium content of erythrocytes after incubation. Sodium entry suppressed by amiloride was obtained from the difference in sodium content in erythrocytes after incubation with and without 3 x 10-4 mol/1 amiloride. This was also the case with the compounds according to the invention.

the results

Inhibition of Na+/H+ exchanger

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Claims (18)

1. Diguanidides of benzenedicarboxylic acids of formula I [image] indicated by that one of the residues R(1), R(2), R(3) and R(4) represents -CO-N=C(NH2)2; and from the remaining residues R(1), R(2), R(3) and R(4) R(1) represents hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, J, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; R(2) and R(4) independently represent hydrogen, F, Cl, Br, J, OH, -CN, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 C-atoms or (CH2)m-R(14); m is 0, 1 or 2 R(14) represents -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy and -NR(15)R( 16); R(15) and R(16) represent hydrogen or -CH3; or R(2) and R(4) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C8)-Alkanoyl, (C2-C8)-Alkoxycarbonyl, Formyl, Carboxy, -CF3, Methyl, Methoxy; R(2) and R(4) independently represent R(22)SO2, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-SO2 ; R(22) and R(28) independently represent methyl or -CF3; R(23), R(24), R(29) and R(30) independently represent hydrogen or methyl; or R(2) and R(4) independently represent -OR(35) or -NR(35)R(36); R(35) and R(36) independently represent hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; or R(35) and R(36) together represent 4-7 methylene groups of which one CH2 group can be substituted with oxygen, -S-, -NH-, -NCH3 or -N-benzyl; R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27); R(25) represents hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms or renyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methylamino and diethylamino; or R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or unsubstituted by 1-3 substituents selected from the group consisting of F, Cl, Cf3, CH3, methoxy, hydroxy, amino, methylamino and dimethylamino; R(26) and R(21) are independently defined as R(25) or represent hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R(5) represents alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, J, X-(CH2)y-CF3 or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from groups consisting of F and Cl, CF3, methyl, methoxy and -NR(6)R(7); R(6) and R(7) independently represent -CH3; X represents a single bond or oxygen; y is zero, 1 or 2; and their pharmaceutically acceptable salts. 2. Compounds of formula I according to claim 1, characterized in that one of the residues R(1), R(2), R(3) and R(4) represents -CO-N=C(NH2)2; and from the remaining residues R(1), R(2), R(3) and R(4) R(1) represents hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, -OR(32), -NR(33)R(34) or CF3; R(32), R(33) and R(34) independently represent hydrogen or methyl; R(2) and R(4) independently represent hydrogen, F, Cl, Br, J, OH, CF, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, alkenyl with 2, 3 or 4 carbon atoms or -(CH2)m-R(14); m is zero, 1 or 2; R(14) represents -(C3,-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy; R(2) and R(4) independently represent pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-Alkanoyl, (C2-C5)-Alkoxycarbonyl, formyl, carboxy, -CF3 and methyl; or R(2) and R(4) independently represent R(22)-SO2-, R(26)-CO- or R(29)R(30)N-SO2; R(22) and R(26) independently represent methyl or CF3; R(29) and R(30) independently represent hydrogen or methyl; or R(2) and R(4) independently represent -OR(35) or -NR(35)R(36); R(35) and R(36) independently represent hydrogen, methyl or ethyl; or R(35) and R(36) together represent 4-5 methylene groups of which one CH2 group can be substituted with oxygen., -S-, -NH-, -NCH3; R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25) R(26) R(27); R(25) represents hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or phenyl, which is not substituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino; or R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with 1-2 substituents Selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino; R(26) and R(27) independently represent hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; R(5) represents alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, CF3 or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F and Cl, -CF3 , methyl, methoxy and dimethylamino 3. Compounds of formula I according to claims 1 or 2, characterized in that one of the residues R(1), R(2), R(3) and R(4) represents -CO-N=C(NH2)2; and from the remaining residues R(1), R(2), R(3) and R(4) R(1) represents hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, R(32), R(33) and R(34) independently represent hydrogen or methyl R(2) and R(4) independently represent hydrogen, F, Cl, OK, CF3, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, or pyrrole-1 -yl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanolyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF2 and methyl; or R(2) and R(4) represent R(22)-SO2-; R(22) represents methyl or –CF3; or R(2) and R(4) independently represent -OR(35) or -NR(35)R(36); R(35) and R(36) independently represent hydrogen, methyl or ethyl; R(3) represents hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27); R(25) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; R(26) and R(27) independently represent hydrogen or methyl; R(5) represents alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3 or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy. 4. Compounds of formula I according to claims 1, 2 or 3, characterized in that one of the residues R(1), R(2), R(3) and R(4) represents -CO-N=C(NH2)2; and from the remaining residues R(1), R(2), R(3) and R(4) R(1) represents hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, F, Cl, CF3, or methoxy; R(2) and R(4) independently represent hydrogen, OH, CF2, -CO-N=C(NH2)2, alkyl with 1, 2, 3 or 4 C-atoms, or pyrrole-1-yl, which unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, J, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl ; R(3) represents hydrogen, -OR(25) or -CR(25)R(26)R(27); R(25) represents hydrogen, alkyl with 1, 2 or 3 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; or R(25) represents -(C1-C9)-heteroaryl which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3 and CH3; R(26) and R(27) independently represent hydrogen or methyl; R(5) represents alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3 or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F and Cl, CF3 and methyl. 5. Process for the production of compound I according to claim 1, characterized in that the compound of formula II [image] in which R(1) to R(5) have the meanings given above for R(1) to R(5), of which however at least one of the substituents R(1) to R(5) represents the indicated COL group, wherein L represents a nucleophilic leaving group that can be easily substituted, chemically transformed with guanidine. 6. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment of arrhythmias. 7. A method for the treatment of arrhythmias, characterized in that an effective amount of the compound I according to claim 1 is mixed with conventional additives and administered in a form suitable for administration. 8. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of heart attack. 9. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of angina pectoris. 10. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of ischemic conditions of the heart. 11. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke. 12. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment of shock conditions. 13. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment of shock conditions. 14. The use of compound I according to claim 1, characterized in that it is used for the production of a medicine used in surgical operations and organ transplants. 15. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine used for preservation and disposal of transplants for surgical procedures. 16. The use of compound I according to claim 1, characterized by the fact that it is used for the production of a drug for the treatment of diseases in which the primary or secondary cause is cell proliferation, and therefore it is used as an antiatherosclerotic agent, an agent against late complications of diabetes, cancer, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, prostate hyperplasia. 17. The use of compound I according to claim 1, characterized in that it is used for the production of a scientific agent for the inhibition of Na+/H+-exchangers, for the diagnosis of hypertension and proliferative diseases. 18. Medicine, characterized in that it contains an effective amount of compound I according to one or more claims 1 to 4.